In her final game in college basketball before she heads to the professional ranks of the WNBA, Clark finished with 30 points, eight rebounds and five assists at Cleveland's Rocket Mortgage Fieldhouse arena.
But it was not enough to stop the University of South Carolina's all-conquering line-up from crowning their undefeated season with a deserved victory.
Clark had led from the front in a blistering start by Iowa that saw the Hawkeyes rattle off 10 unanswered points following the opening tip-off.
A trademark three-point jumper from Clark put Iowa into an 18-7 lead and then two free-throws helped her team into a 20-9 lead shortly afterwards.
But after regrouping following the early onslaught, South Carolina came roaring back to get within two points at 22-20 after Tessa Johnson's layup.
South Carolina moved into the lead for the first time in the game midway through the second quarter after a layup from the 6ft 7in Brazilian centre Kamilla Cardoso.
Although Iowa hit back soon afterwards with another Clark three-point jump shot which put her team 44-40 up, South Carolina refused to roll over, and took the lead after Te-Hina Paopao's third three of the first half made it 47-46.
A rare blunder by Clark then gifted a steal to Raven Johnson, who raced to the basket unopposed for a layup that made it 49-46 at half-time.
Fightback falls short
South Carolina kept their foot down at the start of the second half, jumping out to a nine-point lead at 55-46
Clark led a stirring Iowa rally to make it a two-point game at 57-55, but the Gamecocks responded with an 8-0 run that took the game away from Iowa once more.
South Carolina stretched their lead to 14 points at 76-62 with just over seven minutes remaining, exploiting their advantages in height to never let Iowa back into the contest.
Back-to-back three-pointers from Clark and Gabbie Marshall helped claw the score back to 76-70, but South Carolina would not be denied, their defence slamming the door to keep Iowa at arm's reach down the stretch.
It was the second straight year that Clark's bid to lead Iowa to the national collegiate championship fell short.
Last year Iowa were beaten by Louisiana State despite Clark's dazzling performances.
The Iowa star has emerged as a fully-fledged sporting icon during the past two seasons, her show-stopping skills attracting sellout crowds and shattering US television ratings records.
This season, in her final regular season game, she eclipsed Pete Maravich's 54-year-old all-time college basketball scoring record -- a mark many felt would never be beaten.
She will be chosen by the Indiana Fever with the No.1 pick in the WNBA Draft later this month, and is also a contender to be handed a place in the United States team for the Paris Olympics.
Blue-chip sponsors are scrambling to align their brands behind the "Caitlin Clark Effect", virtually ensuring the young guard will be set for life financially before she even sets foot on a WNBA court.
Clark's rocketing fame has extended beyond the usual parameters of US college basketball, garnering international attention that has been compared to pop icon Taylor Swift.
